Verbascoside: Identification, Quantification, and Potential Sensitization of Colorectal Cancer Cells to 5-FU by Targeting PI3K/AKT Pathway

Abstract

Colorectal cancer (CRC) is the third most common cancer mortality worldwide. Although, 5-Fluorouracil (5-FU)-based chemotherapeutic regimens remain the mainstay for treatment of CRC, intrinsic and acquired resistance to 5-FU is the main reason for treatment failure and relapse. Adjunct or add-on therapy, therefore, should be thought of to enhance responsiveness to 5-FU. Verbascoside (VER) is a phenylethanoid glycoside ingredient present in many Plantago species and was widely used in traditional medicine. VER showed antiproliferative effects in many cancer types including CRC. In the present study, VER in Plantago seeds was identified using UPLC-MS/MS and quantified using newly developed and validated UPLC-DAD followed by investigating its potential sensitization of CRC cells to 5-FU in vitro. The potential impact on PI3K/AKT pathway was also investigated. A synergistic cytotoxic interaction between 5-FU and VER besides G1 cell cycle arrest were detected. Enhanced apoptosis mainly by affecting Bax and Bcl-2 and to a lesser extent Bcl-xL and p53 was also observed. Additionally, 5-FU combined to VER was capable of significantly reducing PI3K and p-AKT/total AKT ratio. Overall, these results suggest a potential role of VER as an adjuvant treatment to decrease the resistance of CRC cells to 5-FU possibly by targeting the PI3K/AKT pathway.

Altered morphokinetics in equine embryos from oocytes exposed to DEHP during IVM

“…Among them, verbascoside (VB), a naturally‐occurring phenylethanoid glycoside (Alipieva, Korkina, Orhan, & Georgiev, ; D'Imperio et al, ) also known as acteoside, is of particular interest. As reported in in vivo studies, VB has antioxidant, antimicrobial, anti‐inflammatory, neuroprotective, and wound healing effects as well as antiproliferative effects in cancer (Attia, El‐Kersh, Wagdy, & Elmazar, ; Serreli et al, ). VB has been shown to protect cells against β‐amyloid‐induced damage via nuclear translocation of the transcription factor NF‐E2‐related factor 2; in these studies VB activated both ERK and PI3 K/Akt, resulting in upregulation of heme oxygenase‐1, a crucial factor in the response to oxidative injury (H. Q. Wang, Xu, & Zhu, ; Li et al, ).…”

6‐O‐(3″, 4″‐di‐O‐trans‐cinnamoyl)‐α‐l‐rhamnopyranosylcatalpol and verbascoside: Cytotoxicity, cell cycle kinetics, apoptosis, and ROS production evaluation in tumor cells

“…Verb has been repeatedly shown to induce apoptosis in Caco‐2, HCT‐116, HT‐29, and U87 cells . Regarding its possible apoptotic mechanisms, Verb upregulated the expression of proapoptotic proteins (caspase‐3, caspase‐8, caspase‐9, Bax, and p53) while downregulating the expression of several antiapoptotic proteins . Furthermore, the ability of Verb to induce ROS production was also observed in mouse A5 spindle carcinoma cells .…”

“…Verb increased subG 1 cell population in Caco‐2 and MKN45 gastric carcinoma cells, 28 but it was also found able to promote cell cycle arrest at the G 0 /G 1 phase in HL‐60 and several glioblastoma (SHG‐44, A172, U87, U373, T98G, and U251) cells . Verb has been repeatedly shown to induce apoptosis in Caco‐2, HCT‐116, HT‐29, and U87 cells . Regarding its possible apoptotic mechanisms, Verb upregulated the expression of proapoptotic proteins (caspase‐3, caspase‐8, caspase‐9, Bax, and p53) while downregulating the expression of several antiapoptotic proteins .…”

Acteoside as a potential therapeutic option for primary hepatocellular carcinoma: a preclinical study

“…Intraperitoneal delivery of acteoside suppressed tumor growth in a melanoma mouse model possibly through inhibiting protein kinase C [12]. In addition, acteoside potentiated the sensitization of colorectal cancer cells to 5-Fluorouracil via targeting PI3K/Akt signaling [13]. Our previous data have also shown an inhibition of melanogenesis by acteoside in B16 melanoma cells [14].…”